Search

Introduction: Preeclampsia (PE) is characterized by an exaggerated systemic inflammatory response (ESIR). Several recent studies by our group and others have demonstrated up-regulation of Toll like receptor 4 (TLR4) in trophoblast, placenta and leukocytes in PE but the exact role of TLR4 in the pathogenesis of PE remains unclear. Objectives: We sought to determine the expression levels of endogenous ligands of TLR4 in plasma and placentas from women with PE vs normotensive pregnant women (NP), and to compare the inflammatory cytokine expression profiles of monocytes from women with PE to NP, in order to identify which of these endogenous ligands of TLR4 may play a functional role in the pathogenesis of PE for further study. Methods: We recruited 16 PE (gestational age=33.6±3.0weeks), 10 normal pregnant (gestational age=31.6±3.8weeks) and 10 non-pregnant women. Plasma levels of endogenous TLR4 ligands-heparan sulfate, hyaluronan, fibronectin, fibrinogen and High mobility group box-1(HMGB1)–were measured by ELISA. Monocytes were isolated from peripheral blood, cultured and stimulated by lipopolysaccharide (LPS; TLR4 bacterial ligand) and endogenous TLR4 ligands, and inflammatory cytokines were measured in supernatant medium by cytometric array. Placental tissue from PE and NP were investigated for the different endogenous ligands by immunohistochemistry. Results: Plasma levels of heparan sulfate and fibronectin did not differ between study groups, but HMGB1 was higher in PE (P <0.05) whilst fibrinogen was significantly lower in PE compared to NP (P <0.05). Stimulation of PE monocytes with LPS resulted in profound secretion of various cytokines: IL-6, IL-8, IL-1β, TNFα and IL-10, in comparison with NP. Moreover, exposure to fibrinogen, but not to other endogenous TLR4 ligands, was also associated with significantly increased production of inflammatory cytokines in PE compared to NP. Also, we observed altered distribution levels of studied endogenous ligands in the placenta from PE vs NP. Conclusion: Our findings of increased inflammatory cytokine expression levels in PE in response to LPS are consistent with upregulation of TLR4 in PE. A similar response induced by fibrinogen suggests an important role for this endogenous ligand of TLR4 in the pathogenesis of PE. Whether our observation of decreased plasma levels of fibrinogen in PE is linked to this observation, or represents increased fibrinogenesis and fibrinolysis associated with the abnormal coagulopathy seen in this condition, is unclear. [Copyright &y& Elsevier]